The extraordinary diversity of HIV-1 poses a major impediment to the development of a practical HIV-1 vaccine. The rapid mutation rate of HIV-1 into multiple quasispecies has led to consideration of centralized (consensus, ancestral, center of the tree) HIV-1 sequences as immunogens for overcoming HIV-1 diversity. We have assembled a highly skilled and experienced team of interinstitutional and multidisciplinary investigators who are committed to HIV-1 vaccine development. This HIVRAD Team has hypothesized that analysis of HIV-1 sequences and selection of artificial centralized sequences, such as consensus sequences, will be a powerful way to design HIV-1 vaccine candidate immunogens. We have achieved proof of concept and demonstrated that synthetic group M consensus env genes, Year 1999 CON6 and Year 2001 CON-S, indeed share T and B cell epitopes with wild-type HIV-1 isolates of multiple subtypes, and induce cross-subtype T and B cell anti-HIV-1 immune responses. The critical question put forth in this grant is "Are centralized HIV-1 genes superior to wild type HIV-1 genes for induction of broadly reactive anti-HIV-1 T or B cell responses"? We will perform comparative immunogenicity experiments of env and gag-pol-nef group M consensus genes with subtype consensus and wildtype genes in small animals and non-human primates. We will systemically enhance the immunogenicity of centralized genes for T cell responses and for B cell neutralizing antibody responses. The overall primary goal of this grant is to comprehensively explore and definitely test the concept of the use of centralized HIV-1 immunogens for HIV-1 vaccine design.